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Xigris, INN-Drotrecogin Alfa

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Xigris, INN-Drotrecogin Alfa SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of Xigris. This scientific discussion has been updated until 1 October 2004. For information on changes after 1 October 2004 please refer to module 8B. 1. Introduction Sepsis is an infection-induced syndrome defined as the presence of two or more features of systemic inflammation (such as fever or hypothermia, leukocytosis or leukopenia, tachycardia, tachypnoea or supranormal minute ventilation). Severe sepsis is defined as being sepsis associated with acute organ dysfunction and it results from a generalised inflammatory and procoagulant response to an infection. Current treatment of sepsis is largely based on administration of antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors, replacement of failing organs). The death rates in some subgroups of patients with sepsis-induced organ failure have decreased; this may be due to the better detection and treatment of the underlying infection or improved supportive care. Nevertheless, it is estimated that the rate of death from severe sepsis ranges from 30 to 50 percent despite advances in critical care. In general and especially during a severe sepsis, the inflammatory and procoagulant host responses to infection are closely related. Inflammatory cytokines, including tumour necrosisauthorised factor α, interleukin- 1β and interleukin-6 are capable of activating coagulation, whereas the procoagulant thrombin is capable of stimulating multiple inflammatory pathways. This may result in diffuse endovascular injury, microvascular thrombosis, organ ischaemia, multiorgan dysfunction and lead to death. Activated protein C is an important modulator of the coagulation and inflammation associated with severe sepsis. Activated protein C is converted from its longerinactive precursor, protein C, by thrombin coupled to thrombomodulin. Activated Protein C modulates the systemic response to infection via three different mechanisms. Firstly, it exerts an antithrombotic effect by inactivating factors Va and VIIIa consequently limiting the generation of nothrombin. Secondly, it indirectly increases the fibrinolytic response by inhibiting the plasminogen-activator inhibitor 1 (PAI-1). PAI-1 is a potent inhibitor of tissue plasminogen activator, the endogenous pathway for lysing a fibrin clot. Finally, as a result of decreased thrombin levels induced by rhAPC, the inflammatory response induced by thrombin is reduced. The conversion of protein C to activated protein C may be impaired during sepsis as a result of the down-regulation of thrombomodulin by inflammatory cytokines. Thus, reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death. product Drotrecogin alfa (activated) is a recombinant human Activated Protein C (rhAPC) which has an identical primary sequence to the endogenous human plasma-derived Activated Protein C. rhAPC has similar properties to those of endogenous human activated protein C. It is an active substance, which has been developed for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care (i.e. severe sepsis). 2. Part II: Chemical, pharmaceutical and biological aspects CompositionMedicinal Xigris is supplied as a powder for solution for intravenous infusion. It is formulated in 5 mg and 20 mg presentation. The active substance contains a recombinant form of human Activated C Protein (rhAPC). 1/36 EMEA 2004 The detailed composition of both presentations is given in the table below Ingredient Quantity per Vial Quantity per Vial Function Active Ingredient recombinant human 20 mg 5 mg Active Ingredient Activated Protein C Other Ingredients Sodium Chloride 152 mg 38 Bulking Agent/ Solution-State Stabiliser Citrate 1 30.2 mg 7.56 mg Buffering Agent Sucrose 120 mg 30 mg Bulking Agent/ solid-state Stabiliser 1 The source of citrate (citrate ion) is a buffer system composed of Citric Acid, Ph.Eur., USP, Sodium Citrate, Ph.Eur., USP, hydrochloric acid, and sodium hydroxide. The sourceauthorised of Citric Acid, Ph.Eur., USP is the rhAPC Drug Substance. The 5 mg and 20 mg presentations are prepared using the same drug product manufacturing solution and thus contain the same excipients at the same relative ratios. The two strengths are prepared by varying the amount of filling solution for lyophilisation to yield 5 mg and 20 mg rhAPC. After reconstitution the solution exhibits the same strength with respect to all ingredients of the medicinal product. longer In order to assure the nominal dose delivery, a vial of the proposed commercial product, 5mg will typically contain a 6 % excess (5.30mg rhAPC/vial)no and a vial of the proposed commercial 20 mg presentation will typically contain an overfill of 4.05% (20.81 mg rhAPC/vial). Reconstitution studies have been performed with regard to dissolution, stability, microbial quality and compatibility with different dispensing material. Container The container is the same forproduct both presentations: an ammonium sulfate treated type I glass vial of 5 ml (5 mg rhAPC) and 20 ml (20 mg rhAPC) closed with butyl rubber stoppers and sealed with aluminium seals with flip caps. The container closure systems are adequately described and meet the Ph. Eur. Standards for use with parenteral products. Clinical trial formulae The used clinical trial formulae are well described. Production and control of starting materials SpecificationsMedicinal Tests and specifications for rhAPC drug substance have been established in accordance with the nomenclature and principles described in the ICH (Q6B) guidance document “Specifications, Test Procedures, and Acceptance Criteria for Biotechnology and Biological Products.” The specification limits for rhAPC Drug Substance were established based on experience with the manufacture of this product by Eli Lilly and Company and Lonza Biologics Inc. In particular, they were established based on extensive characterization of the rhAPC reference standard, routine testing and additional characterization of clinical trial lots and full-scale consistency lots, stability studies, and analytical methods validation 2/36 EMEA 2004 The proposed release specifications are considered adequate to ensure the quality of the produced active substance batches. Development genetics Gene isolations strategy and rationale The cDNA used for the generation of the production cell line for Lilly rhAPC [drotrecogin alfa (activated)] was derived from the liver of a healthy male donor organ. Since the liver is the primary biosynthetic source of circulating plasma Protein C, it was expected to be the best source for mRNA. Part of the nucleotide sequence of the plasmid includes the coding for a preproprotein of 461 amino acids, which corresponds to the complete coding sequence of the human Protein C gene with short flanking sequences. Description of the host cell line The human cell line, HEK293, into which the Protein C expression vectors were introduced, was purchased from American Tissue Culture Collection (ATCC). HEK293 from ATCC was transformed with adenovirus 5 DNA. The Ad5 DNA originally used to transform the cell line is classified as a non- oncogenic (Group C) adenovirus. The rationale for the use of the cell line for the production of recombinant human Protein C is based on the ability of this cell to correctly perform a series of complex post-translational modifications that are required for functional activity (see below). authorised Preparation of the production cell line Construction of the expression vector The construction of the final expression vectors with all intermediary steps is extensively described. The transcription of the human Protein C has been described adequately. A restriction/function map of the plasmid pGTC is shownlonger in the dossier and the details of origin and sites of the exact fragments contained in the vector have also been presented. Selection and cloning of production cell line no The generation of the production line was accomplished by first isolating an initial Protein C- producing line in order to produce a clone, capable of higher production of human recombinant Protein C. This clone was subcloned to obtain a single cell isolate which was further used to generate the initial certified Master Cell Bank (MCB). The Manufacturer Working Cell Bank (WCB) was then generated from the MCB. Description of the cell line The initial cell line was extensivelyproduct tested and found to be negative for the presence of human and nonhuman adventitious agents. Preparation and testing of cells at the limit of in-vitro age for production A number of tests were achieved in order to demonstrate the stability of the expression construct for rhPC. The evaluation of the stability of the expression construct is based on comparisons of the tests results from the MCB, the WCB and the cells at or beyond the limit of in-vitro age of production. In general, the manufacturer has achieved a clear description of the whole genetic development, includingMedicinal plasmids constructions and cell lines isolation, that allows understanding of the way for the final isolation of the producing cell line. Cell Bank System The whole cell bank system is adequately described. Characterization testing of all cell banks has been performed in accordance with ICH Guideline Q5D and study reports are included. The testing protocol for new WCB is fully documented and considered to be adequate. 3/36 EMEA
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